Therapeutic ((bicylicheteroaryl)imidazolyl) methylheteroaryl compounds

ABSTRACT

Disclosed herein is a compound of the formula (I) therapeutic methods, compositions, and medicaments related thereto are also disclosed.

CROSS REFERENCE

This is a national stage application under 35 U.S.C. §371 of PCT patentapplication PCT/US08/64284, filed on May 21, 2008, which claims thebenefit of U.S. Provisional Patent Application U.S. application Ser. No.60/939,781, filed May 23, 2007, each of which is hereby incorporated byreference in its entirety.

BACKGROUND

Human adrenergic receptors are integral membrane proteins which havebeen classified into two broad classes, the alpha and the betaadrenergic receptors. Both types mediate the action of the peripheralsympathetic nervous system upon binding of catecholamines,norepinephrine and epinephrine.

Norepinephrine is produced by adrenergic nerve endings, whileepinephrine is produced by the adrenal medulla. The binding affinity ofadrenergic receptors for these compounds forms one basis of theclassification: alpha receptors tend to bind norepinephrine morestrongly than epinephrine and much more strongly than the syntheticcompound isoproterenol. The preferred binding affinity of these hormonesis reversed for the beta receptors. In many tissues, the functionalresponses, such as smooth muscle contraction, induced by alpha receptoractivation are opposed to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and betareceptors was further highlighted and refined by the pharmacologicalcharacterization of these receptors from various animal and tissuesources. As a result, alpha and beta adrenergic receptors were furthersubdivided into α₁, α₂, β₁, and β₂ subtypes. Functional differencesbetween α₁ and α₂ receptors have been recognized, and compounds whichexhibit selective binding between these two subtypes have beendeveloped. Thus, in published international patent application WO92/0073, the selective ability of the R(+) enantiomer of terazosin toselectively bind to adrenergic receptors of the α₁ subtype was reported.The α₁/α₂ selectivity of this compound was disclosed as beingsignificant because agonist stimulation of the α₂ receptors was said toinhibit secretion of epinephrine and norepinephrine, while antagonism ofthe α₂ receptor was said to increase secretion of these hormones. Thus,the use of non-selective alpha-adrenergic blockers, such asphenoxybenzamine and phentolamine, was said to be limited by their α₂adrenergic receptor mediated induction of increased plasma catecholamineconcentration and the attendant physiological sequelae (increased heartrate and smooth muscle contraction). For a further general background onthe α-adrenergic receptors, the reader's attention is directed to RobertR. Ruffolo, Jr., α-Adrenoreceptors: Molecular Biology, Biochemistry andPharmacology, (Progress in Basic and Clinical Pharmacology series,Karger, 1991), wherein the basis of α₁/α₂ subclassification, themolecular biology, signal transduction, agonist structure-activityrelationships, receptor functions, and therapeutic applications forcompounds exhibiting a-adrenergic receptor affinity is explored.

The cloning, sequencing and expression of alpha receptor subtypes fromanimal tissues has led to the subclassification of the α₁adrenoreceptors into α_(1A), α_(1B) and α_(1D). Similarly, the α₂adrenoreceptors have also been classified α_(2A), α_(2B), and α_(2C)receptors. Each α₂ receptor subtype appears to exhibit its ownpharmacological and tissue specificities. Compounds having a degree ofspecificity for one or more of these subtypes may be more specifictherapeutic agents for a given indication than an α₂ receptorpan-agonist (such as the drug clonidine) or a pan-antagonist.

Among other indications, such as the treatment of glaucoma,hypertension, sexual dysfunction, and depression, certain compoundshaving alpha₂ adrenergic receptor agonist activity are known analgesics.However, many compounds having such activity do not provide the activityand specificity desirable when treating disorders modulated by alpha₂adrenoreceptors. For example, many compounds found to be effectiveagents in the treatment of pain are frequently found to have undesirableside effects, such as causing hypotension and sedation at systemicallyeffective doses. There is a need for new drugs that provide relief frompain without causing these undesirable side effects. Additionally, thereis a need for agents which display activity against pain, particularlychronic pain, such as chronic neuropathic and visceral pain.

DESCRIPTION OF THE INVENTION

Disclosed herein is a compound of the formula

wherein A is monocyclic heteroaryl having 0, 1, 2, or 3 substituents;and B is a fused ring system consisting of:

-   -   a phenyl ring which attaches to the remainder of the molecule,    -   a second heterocyclic five-, or six-membered ring which is fused        to the phenyl ring,    -   and 0, 1, 2, or 3 substituents which attach to one or both of        the phenyl ring and the second ring;        wherein each substituent independently consists of from 0 to 8        carbon atoms, from 0 to 3 oxygen atoms, from 0 to 3 halogen        atoms, from 0 to 2 nitrogen atoms, from 0 to 2 sulfur atoms, and        from 0 to 24 hydrogen atoms.

Unless otherwise indicated, reference to a compound should be construedbroadly to include pharmaceutically acceptable salts, prodrugs,tautomers, alternate solid forms, and non-covalent complexes of achemical entity of the depicted structure or chemical name.

A pharmaceutically acceptable salt is any salt of the parent compoundthat is suitable for administration to an animal or human. Apharmaceutically acceptable salt also refers to any salt which may formin vivo as a result of administration of an acid, another salt, or aprodrug which is converted into an acid or salt. A salt is anassociation of an ionic form of the compound, such as a conjugate acidor base, with a corresponding amount of counter-ions. Salts can formfrom or incorporate one or more deprotonated acidic groups, one or moreprotonated basic groups (e.g. amines), or both (e.g. zwitterions).

A prodrug is a compound which is converted to a therapeutically activecompound after administration. While not intending to limit the scope ofthe invention, conversion may occur by hydrolysis of an ester group orsome other biologically labile group. Prodrug preparation is well knownin the art. For example, “Prodrugs and Drug Delivery Systems,” which isa chapter in Richard B. Silverman, Organic Chemistry of Drug Design andDrug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp.496-557, provides further detail on the subject.

Tautomers are isomers that are in rapid equilibrium with one another.They often, but do not necessarily, include a transfer of a proton,hydrogen atom, or hydride ion. For example, the structures herein areintended to include, but are not limited to, the tautomeric forms shownbelow.

Unless stereochemistry is explicitly depicted, a structure is intendedto include every possible stereoisomer, both pure or in any possiblemixture.

Alternate solid forms are different solid forms than those that mayresult from practicing the procedures described herein. For example,alternate solid forms may be polymorphs, different kinds of amorphoussolid forms, glasses, and the like.

Non-covalent complexes are complexes that may form between the compoundand one or more additional chemical species that do not involve acovalent bonding interaction between the compound and the additionalchemical species. They may or may not have a specific ratio between thecompound and the additional chemical species. Examples might includesolvates, hydrates, charge transfer complexes, and the like.

A is monocyclic heteroaryl, meaning an aromatic ring with one or morenitrogen, sulfur, or oxygen atoms in the ring. Typical examples ofheteroaryl include pyridyl, thienyl, furyl, pyrrolyl, pyrrolidinyl,imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidinyl, and pyrazinyl.A can be unsubstituted, or substituted with up to 3 substituents.

B is a fused ring system consisting of: a phenyl ring which attaches tothe remainder of the molecule, a second heterocyclic five-, orsix-membered ring which is fused to the phenyl ring, and 0, 1, 2, or 3substituents which attach to one or both of the phenyl ring and thesecond ring.

In other words, structures such as the ones shown below arecontemplated. Bond “a” connects the phenyl ring of B to the rest of themolecule. The second heterocyclic five-, or six membered ring fused tothe phenyl ring is represented by Z. Finally, R¹R², and R³ representhydrogen atoms or substituents subject to the constraints given herein.

The heterocyclic five- or six-membered ring has at least one nitrogen,sulfur, or oxygen atom in the ring. It can be heteroaromatic ornon-aromatic. The substituents may be attached to the phenyl ring, theheteroaromatic ring, or substituents may be attached to both rings.

Typical examples of B include: quinolinyl, quinoxalinyl, indolyl,benzothienyl, benzofuryl, benzofuranyl, benzodioxolyl,2,3-dihydrobenzo[b][1,4]dioxin-6-yl, and the like.

Quinolinyl includes isoquinolinyl and other isomers, such as thestructures shown below, either unsubstituted as depicted or havingsubstituents subject to the constraints herein.

The substituents of A and B are subject to the same constraints.However, the substituents are independent, meaning that A and B may havethe same or different substituents; the substituents on A may be thesame or different from one another; and the substituents on B may be thesame or different from one another.

Subject to the constraints described herein (e.g. limits on the numberof atoms for a substituent), examples of substituents include, but arenot limited to:

Hydrocarbyl, meaning a moiety consisting of carbon and hydrogen only,including, but not limited to:

-   -   a. alkyl, meaning hydrocarbyl having no double or triple bonds,        including, but not limited to:        -   linear alkyl, e.g. methyl, ethyl, n-propyl, n-butyl,            n-pentyl, n-hexyl, etc.,        -   branched alkyl, e.g. iso-propyl, t-butyl and other branched            butyl isomers, branched pentyl isomers, etc.,        -   cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl,            cyclohexyl, etc.,        -   combinations of linear, branched, and/or cycloalkyl;    -   b. alkenyl, e.g. hydrocarbyl having 1 or more double bonds,        including linear, branched, or cycloalkenyl    -   c. alkynyl, e.g. hydrocarbyl having 1 or more triple bonds,        including linear, branched, or cycloalkenyl;    -   d. combinations of alkyl, alkenyl, and/or akynyl

alkyl-CN, such as —CH₂—CN, —(CH₂)₂—CN; —(CH₂)₃—CN, and the like;

hydroxyalkyl, i.e. alkyl-OH, such as hydroxymethyl, hydroxyethyl, andthe like;

ether substituents, including —O-alkyl, alkyl-O-alkyl, and the like;

thioether substituents, including —S-alkyl, alkyl-S-alkyl, and the like;

amine substituents, including —NH₂, —NH-alkyl, —N-alkyl¹alkyl² (i.e.,alkyl¹ and alkyl² are the same or different, and both are attached toN), alkyl-NH₂, alkyl-NH-alkyl, alkyl-N-alkyl¹alkyl², and the like;

aminoalkyl, meaning alkyl-amine, such as aminomethyl (—CH₂-amine),aminoethyl, and the like;

ester substituents, including —CO₂-alkyl, —CO₂₋phenyl, etc.;

other carbonyl substituents, including aldehydes; ketones, such as acyl(i.e.

and the like; in particular, acetyl, propionyl, and benzoyl substituentsare contemplated;

phenyl or substituted phenyl;

fluorocarbons or hydroflourocarbons such as —CF₃,₋CH₂CF₃, etc.; and

—CN;

combinations of the above are also possible, subject to the constraintsdefined;

Alternatively, a substituent may be —F, —Cl, —Br, or —I.

In particular, alkyl having from 1 to 8 carbon atoms is contemplated asa substituent.

Alternatively, alkyl having from 1 to 4 carbon atoms is contemplated;

Substituents must be sufficiently stable to be stored in a bottle atroom temperature under a normal atmosphere for at least 12 hours, orstable enough to be useful for any purpose disclosed herein.

If a substituent is a salt, for example of a carboxylic acid or anamine, the counter-ion of said salt, i.e. the ion that is not covalentlybonded to the remainder of the molecule is not counted for the purposesof the number of heavy atoms in a substituent. Thus, for example, thesalt —CO₂ ⁻Na⁻ is a stable substituent consisting of 3 heavy atoms, i.e.sodium is not counted. In another example, the salt —NH(Me)₂ ⁺Cl⁻ is astable substituent consisting of 3 heavy atoms, i.e. chlorine is notcounted.

In one embodiment, A is pyridinyl, meaning that compounds of structuressuch as those shown below are contemplated.

In these structures, R¹, R², and R³ are substituents as defined herein.

In another embodiment, A is thienyl, meaning that compounds ofstructures such as those shown below are contemplated.

In these structures, R¹, R², and R³ are substituents as defined herein.

In another embodiment, A is furyl, meaning that compounds of structuressuch as those shown below are contemplated.

In these structures, R¹, R², and R³ are hydrogen or substituents, asdefined herein.

In one embodiment, A is pyridinyl, thienyl, furyl, or pyrrolyl.

In another embodiment, each substituent is independently —H, alkylhaving from 1 to 8 carbon atoms, —F, —Cl, —Br, —CH₂OH, an amine havingfrom 0 to 8 carbon atoms, —CH₂CN, —CF₃, or acyl having from 1 to 8carbons.

In another embodiment, A is pyridinyl.

In another embodiment, B is quinolinyl.

In another embodiment each substituent of B is —H, —F, —Cl, —Br, —CH₃,—NHCH₃, or —CF₃.

Hypothetical examples of useful compounds include those shown below.

Synthetic Methods Method A: Procedure for the preparation of8-((1H-imidazol-5-yl)(pyridin-2-yl)methyl)quinoline (301)

A solution of 4-iodo-1-tritylimidazole (commercially available) 5.2 g,11.94 mmol) in dichloromethane (80 mL) at −10° C. was treated with ethylmagnesium bromide (3.98 mL, 11.94 mmol, 3M in ether) and allowed toreact for 45 m. A solution of quinoline-8-carbaldehyde, (Intermediate11) (1.5 g, 9.55 mmol) in dichloromethane was added via syringe at −10°C. and stirred for 16 h at room temperature. The mixture was quenchedwith water (50 mL) and a sat. solution of ammonium chloride (50 mL) andsubjected to an aqueous work-up. The residue was purified bychromatography on silica gel with 3% NH₃-MeOH: CH₂Cl₂ to give to givequinolin-8-yl(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 12) as asolid, (3.7 g 82.7%).

A mixture of quinolin-8-yl(1-trityl-1H-imidazol-5-yl)methanol,(Intermediate 12) 3.7 g, 7.9 mmol) in CH₂Cl₂ (50 mL) was treated withmanganese(IV) oxide, activated (commercially available from Aldrich):MnO₂ (4.1 g, 47.4 mmol) at room temperature. The mixture was heated to60° C. for 2 h. The mixture was then cooled to room temperature andfiltered through celite and the solvent was removed under vacuum to getquinolin-8-yl(1-trityl-1H-imidazol-5-yl)methanone, (Intermediate 13)(3.6 g, 97%).

A solution of 2-iodo-pyridine (commercially available) (307 mg, 1.5mmol) in dichloromethane (20 mL) at room temperature was treated withethyl magnesium bromide (0.50 mL, 1.5 mmol, 3M in ether) and allowed toreact for 45 m. A solutionquinolin-8-yl(1-trityl-1H-imidazol-5-yl)methanone, (Intermediate 13)(465 mg, 1.00 mmol) in dichloromethane was added via syringe at roomtemperature and the reaction mixture was then stirred at roomtemperature for 16 h. The mixture was quenched with water (20 mL) and asat. solution of ammonium chloride (20 mL). The residue was isolated ina typical aqueous to givepyridin-2-yl(quinolin-8-yl)(1-trityl-1H-imidazol-5-yl)methanol,(Intermediate 14) (385 mg, crude).

A mixture ofpyridin-2-yl(quinolin-8-yl)(1-trityl-1H-imidazol-5-yl)methanol(Intermediate 14) (385 mg, 0.70 mmol) in 57% aqueous HI (10 mL) andiPrOH (2 mL) was added red phosphorus (219 mg, 7.0 mmol) in a resealabletube was heated at 160° C. for 16 h. The mixture was then cooled to roomtemperature and poured into ice-water, which was then basified with NaOHand diluted with CHCl₃. The residue was isolated in a typical aqueousworkup using CHCl₃ and purified by MPLC with 5 to 15% MeOH:CH₂Cl₂ togive 8-((1H-imidazol-5-yl)(pyridin-2-yl)methyl)quinoline, (658) as asolid, 236 mg (61% in two steps). ¹HNMR (CD₃OD, 300 MHz) δ 8.82 (dd,J=1.8, 4.5 Hz, 1H), 8.43 (dd, J=1.8, 5.7 Hz, 1H), 8.28 (dd, J=1.8, 8.4Hz, 1H), 7.83 (dd, J=4.0, 7.8 Hz, 1H), 7.73-7.70 (m, 2H), 7.68-7.43 (m,3H), 7.25-7.21 (m, 2H), 7.03 (s, 1H), 6.52 (s, 1H).

Biological Data

Receptor Selection and Amplification Technology (RSAT) Assay

The RSAT assay measures a receptor-mediated loss of contact inhibitionthat results in selective proliferation of receptor-containing cells ina mixed population of confluent cells. The increase in cell number isassessed with an appropriate transfected marker gene such asβ-galactosidase, the activity of which can be easily measured in a96-well format. Receptors that activate the G protein, Gq, elicit thisresponse. Alpha2 receptors, which normally couple to Gi, activate theRSAT response when coexpressed with a hybrid Gq protein that has a Gireceptor recognition domain, called Gq/i5.

NIH-3T3 cells are plated at a density of 2×106 cells in 15 cm dishes andmaintained in Dulbecco's modified Eagle's medium supplemented with 10%calf serum. One day later, cells are cotransfected by calcium phosphateprecipitation with mammalian expression plasmids encodingp-SV-β-galactosidase (5-10 μg), receptor (1-2 μg) and G protein (1-2μg). 40 μg salmon sperm DNA may also be included in the transfectionmixture. Fresh media is added on the following day and 1-2 days later,cells are harvested and frozen in 50 assay aliquots. Cells are thawedand 100 μl added to 100 μl aliquots of various concentrations of drugsin triplicate in 96-well dishes. Incubations continue 72-96 hr at 37° C.After washing with phosphate-buffered saline, β-galactosidase enzymeactivity is determined by adding 200 μl of the chromogenic substrate(consisting of 3.5 mM o-nitrophenyl-β-D-galactopyranoside and 0.5%nonidet P-40 in phosphate buffered saline), incubating overnight at 30°C. and measuring optical density at 420 nm. The absorbance is a measureof enzyme activity, which depends on cell number and reflects areceptor-mediated cell proliferation. The efficacy or intrinsic activityis calculated as a ratio of the maximal effect of the drug to themaximal effect of a standard full agonist for each receptor subtype.Brimonidine, also called UK14304, the chemical structure of which isshown below, is used as the standard agonist for the alpha_(2A),alpha_(2B) and alpha_(2C) receptors. The EC₅₀ is the concentration atwhich the drug effect is half of its maximal effect.

The results of the RSAT assay with several exemplary compounds of theinvention are disclosed in Table 1 above together with the chemicalformulas of these exemplary compounds. EC₅₀ values are nanomolar. NDstands for “not determinable” at concentrations less than 10 micromolar.IA stands for “intrinsic activity.”

TABLE 1 Biological Data: Intrinsic Activity potency nM efficacy (EC50)Structure Alpha 2A Alpha 2B Alpha 2C

ND (0.15) 22 (1.00) 275 (0.60)

576 (0.50) 2.15 (1.29) 123 (1.16)

ND (0.13) 348 (0.45) ND (0.22)

ND (0.12) 231 (0.90) ND (0.33)

ND 771 (0.65) ND (0.18)

nd (0.23) 9.12 (0.87) 159 (0.86)

430 (0.46) 10 (1.13) 157 (1.12)

The following compounds have been synthesized by the method describedabove:

8-((1H-imidazol-5-yl)(pyridin-3-yl)methyl)quinoline, 302

¹H NMR (300 MHz, CDCl₃): δ 8.82 (dd, J=1.8, 4.5 Hz, 1H), 8.42 (d, J=2.1Hz, 1H), 8.33 (dd, J=1.5, 4.8 Hz, 1H), 8.28 (dd, J=1.8, 8.1 Hz, 1H),7.83 (dd, J=1.5, 8.1 Hz, 1H), 7.69 (d, J=1.2, Hz, 1H), 7.67-7.63 (m,1H), 7.56-7.43 (m, 3H), 7.30 (dd, J=4.8, 8.1 Hz, 1H), 6.95 (s, 1H), 6.57(s, 1H).

5-((1H-imidazol-5-yl)(pyridin-2-yl)methyl)quinoline, 116

¹H NMR (300 MHz, CDCl₃): δ 8.82 (dd, J=1.5, 4.2 Hz, 1H), 8.56 (d, J=8.7Hz, 1H), 8.51-8.49 (m, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.77-7.66 (m, 3H),7.47 (dd, J=4.5, 8.7 Hz, 1H), 7.32-7.26 (m, 1H), 7.20 (t, J=8.1 Hz, 2H),6.54 (s, 1H), 6.39 (s, 1H).

5-((1H-imidazol-4-yl)(pyridin-3-yl)methyl)quinoline, 319

¹H NMR (300 MHz, CDCl₃): δ 8.81 (dd, J=4.5, 1.8 Hz, 1H), 8.43 (d, J=2.1Hz, 1H), 8.41 (dd, J=4.8, 1.8 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 7.96 (d,J=8.7 Hz, 1H), 7.56 (dd, J=8.7, 7.5 Hz, 1H), 7.48 (s, 1H), 7.39 (dt,J=8.1, 1.8 Hz, 1H), 7.28 (dd, J=8.4, 3.9 Hz, 1H), 7.16 (dd, J=7.8, 5.1Hz, 1H), 7.08 (d, J=6.9 Hz, 1H), 6.29 (s, 1H), 6.12 (s, 1H).

5-((1H-imidazol-4-yl)(pyridin-4-yl)methyl)quinoline, 320

¹H NMR (300 MHz, CDCl₃): δ 8.82 (dd, J=4.2, 1.5 Hz, 1H), 8.46-8.44 (m,2H), 8.23 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.57 (dd, J=8.4,7.2 Hz, 1H), 7.53 (s, 1H), 7.28 (dd, J=8.7, 4.5 Hz, 1H), 7.11-7.06 (m,3H), 6.34 (s, 1H), 6.09 (s, 1H).

Methods of formulating these compounds are well known in the art. Forexample, U.S. Pat. No. 7,141,597 (especially column 10, line 27 tocolumn 14, line 47) contains information that may be used for generalguidance. Similar relevant information is also available in numerousother sources. The biological activity of the compounds disclosed herein(e.g. Table 1) may be used for additional general guidance on dosage,depending on the particular use of a compound.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the claims.

1. A compound of the formula

wherein A is monocyclic heteroaryl having 0, 1, 2, or 3 substituents;and B is a fused ring system consisting of: a. a phenyl ring, whereinthere is a single covalent bond between a carbon atom of the phenyl ringand the carbon atom attached to A and the imidazolyl ring; b. a secondheterocyclic six-membered ring which is fused to the phenyl ring, and c.0, 1, 2, or 3 substituents which attach to one or both of the phenylring and the second ring; wherein each substituent independentlyconsists of from 0 to 8 carbon atoms, from 0 to 3 oxygen atoms, from 0to 3 halogen atoms, from 0 to 2 nitrogen atoms, from 0 to 2 sulfuratoms, and from 0 to 24 hydrogen atoms.
 2. The compound of claim 1wherein A is pyridinyl, thienyl, furyl, or pyrrolyl.
 3. The compound ofclaim 2 wherein B is quinolinyl, indolyl, benzothienyl, benzofuryl,benzofuranyl, benzodioxolyl, or 2,3-dihydrobenzo[b][1,4]dioxin-6-yl. 4.The compound of claim 3 wherein each substituent is independently —H,alkyl having from 1 to 8 carbon atoms, —F, —Cl, —Br, —CH₂OH, an aminehaving from 0 to 8 carbon atoms, —CH₂CN, —CF₃, or acyl having from 1 to8 carbons.
 5. The compound of claim 4 wherein A is pyridinyl.
 6. Thecompound of claim 5 wherein B is quinolinyl.
 7. The compound of claim 6wherein each substituent of B is —H, —F, —Cl, —Br, —CH₃, —NHCH₃, or—CF₃.
 8. The compound of claim 7 having the formula


9. The compound of claim 7 having the formula


10. The compound of claim 7 having the formula


11. The compound of claim 7 having the formula


12. The compound of claim 7 having the formula


13. A method of treating pain comprising administering a compoundaccording to claim 1 to a mammal in need thereof.
 14. The method ofclaim 13 wherein the pain is chronic pain.
 15. The method of claim 14wherein the pain is chronic neuropathic pain or visceral pain.
 16. Adosage form comprising a compound according to claim 1.